In vivo suppression of SIV-mediated immune activation

描述(由申请人提供)：免疫激活水平的差异已被确定为艾滋病敏感物种和抗药性物种之间唯一更显着的差异。在某些物种中，较高的免疫激活水平与HIV和SIV的致病性相关，可能是因为增加的CD4+T细胞免疫激活会导致免疫激活介导的细胞凋亡增加，并伴随着CD4+T细胞的耗尽。免疫激活可由多种机制诱导，包括病毒抗原持续刺激免疫反应，和/或产生免疫激活细胞因子和趋化因子。我们已经证明，HIV和SIV感染调节灵长类APC和T细胞基因的表达，并且至少有一部分在感染者和RM IDC中重新编程的干扰素刺激基因(ISG)在艾滋病抗性物种的APC中不受SIV感染的影响。我们曾推测，免疫激活的诱导和维持可能依赖于HIV或SIV诱导的细胞通路，导致免疫激活细胞因子和趋化因子的产生，并已在体外证明了这一点。P38MAPK在HIV和SIV感染中被激活，是诱导ISG的关键途径，并在体内与HIV和SIV感染在艾滋病易感灵长类动物中产生的一些病理有关。我们确定了病毒蛋白TAT如何直接调节细胞蛋白，从而导致p38MAPK途径的激活。由于目前还没有有效的药物可以阻断TAT的活性，p38 MAPK的抑制剂也是可用的，并且目前已经在针对其他疾病的人体试验中进行了测试，因此我们打算评估在针对不同人类疾病的试验中使用p38抑制剂治疗SIV感染的猕猴的效果，该抑制剂已被证明可以降低免疫活性。我们的目标是：1.从纵向上评价PH-797804介导的抑制p38MAPK对四种SIV感染的RM的免疫激活的影响，作为主要终点评估RM PBMC、淋巴结和直肠黏膜活检组织中与免疫激活相关的表面分子的基因表达谱和表达以及血清中炎症细胞因子和趋化因子的水平；2.作为次要终点评估治疗对病毒载量、中央记忆CD_4+T细胞的保存以及可能对疾病进展的影响。这项工作可以为在临床前和临床试验中测试p38 MAPK抑制剂以及鼓励有效的TAT抑制剂的开发提供理论基础。

DESCRIPTION (provided by applicant): Differences in levels of immunoactivation have been identified as the single more significant difference between AIDS susceptible and resistant species. Higher levels of immunoactivation correlate with HIV and SIV pathogenicity in certain species, possibly because increased CD4+ T cell immunoactivation would result in increased immunoactivation-mediated apoptosis, accompanied by CD4+ T cell depletion. Immunoactivation can be induced by a variety of mechanisms, including persistent stimulation of immune responses by viral antigens, and/or production of immunoactivating cytokines and chemokines. We have shown that HIV and SIV infections modulates primate APC and T-cell gene expression and that at least a subset of the IFN-stimulated genes (ISG), reprogrammed in infected human and RM iDC, are not affected by SIV infection in APC of AIDS resistant species. We had postulated that induction and maintenance of immune activation could depend on the induction by HIV or SIV of cell pathways leading to the production of immunoactivating cytokines and chemokines and have shown that this is the case in vitro. p38 MAPK, which has been reported to be activated in HIV and SIV infection, is key in the pathway of induction of ISG and is associated in vivo with the some of the pathology produced by HIV and SIV infection in AIDS susceptible primates. We identified how the viral protein Tat directly modulates cellular proteins that lead to the activation of the p38 MAPK pathway. As no effective drugs that block Tat activity exist and inhibitors of p38 MAPK are available and currently tested in human trials for other diseases, we intend to evaluate the effects of treating SIV-infected macaques with a p38 inhibitor that has been shown to reduce immune activation in trials for different human diseases. Our goal is to 1. To evaluate longitudinally the impact that in vivo PH-797804-mediated inhibition of p38 MAPK has on immune activation in four SIV-infected RM by evaluating as primary end points the gene expression profiles and expression of surface molecules linked to immune activation in RM PBMC, lymph node and rectal mucosa biopsies and the serum levels of inflammatory cytokines and chemokines; 2. to evaluate as secondary end points the effect that the treatment has on viral loads, preservation of central memory CD4+ T cells, and possibly on disease progression. This work could provide the rationale for testing p38 MAPK inhibitors in preclinical and clinical trials and for encouraging the development of effective Tat inhibitors.